1. Field of the Invention
This invention is in the field of pharmacology, and relates specifically to the pharmacological treatment of conditions associated with the constriction of small blood vessels.
2. Description of the Prior Art
Vasoconstriction, or the reduction in the cross-sectional area of the lumen of small blood vessels, is a potentially lethal condition arising in a variety of pathologies, and is due either to vasospasm, inadequate vasodilatation, thickening of the vessel wall, or the accumulation of flow-restricting materials on the internal wall surfaces or within the wall itself. Vasoconstriction is a major factor in various diseases, including progressive generalized atherogenesis, heart attack, stroke, hypertension, glaucoma, migraine, hypertension of pregnancy, and diabetes mellitus, among others.
Vasoconstriction originates in a variety of ways. One example is the local conversion by dysfunctional endothelium of circulating low density lipoproteins (LDL) into oxidatively activated low density lipoproteins ((ox)LDL). (ox)LDL is internalized via cellular macrophage scavenger receptors creating lipid-engorged macrophages, called "foam cells." These cells are bound to the vascular endothelium and subendothelium, release a variety of growth factors and cytokines that stimulate vascular smooth muscle cell proliferation and trigger the increase of the local endothelial expression of leukocyte adhesion molecules and leukocyte chemotaxants; all precursors of progressive vascular atherosclerosis and its subsequent reduction of vascular cross-sectional area.
Another example is the endothelial cell release of endothelin-1, a powerful arterial vasoconstrictor. Repetitive or prolonged vasospasm results in mechanical hypertrophy, proliferation of the microvascular smooth muscle fibers (hyperplasia), and a consequent secondary thickening of the vascular media wall. Various mechanisms leading to the release of endothelin-1 are known. These mechanisms include: its induction by the increase in availability of intracellular ionic calcium which results from the opening of calcium channels in dysfunctional endothelium; and its induction by the reactive sulfhydryl group of homocysteine which is released by endothelial cells that have been damaged by "foam cells."
A third example of vasoconstriction is the activation, rolling, local accumulation, and eventual cell-to-cell adhesion of platelets and white blood cells on the endothelial surface and within the subendothelium. This accumulation stimulates the platelets to activate and attract those macrophages which will be converted into "foam cells," initiate smooth muscle cell proliferation, and release additional leukocyte chemoattractants. These events result in additive vasospastic and mechanical vascular blockade.
A fourth example is the conversion of glucose to sorbitol, which causes irregular vasoconstriction or vasodilatation due to the osmotically induced death of vascular pericytes in diabetes mellitus.
Magnesium is known to reduce the risk of vasoconstriction and also to influence a broad diversity of functions in physiology and pathology. In addition to improving adenosine triphosphate (cATP) energy-requiring metabolism and anaerobic phosphorylation, magnesium suppresses the conversion of LDL to (ox)LDL, reduces platelet and white blood cell aggregation and adhesion, and serves as a physiological calcium channel blocker, thereby reducing the production of endothelin-1 by atherosclerotic endothelial cells. Its action in improving cATP and prostacyclin synthesis of EDRF (Endothelial Derived Relaxation Factor--otherwise referred to as nitric oxide), reduces vasoconstriction by actively inducing vasorelaxation.
The recommended daily allowance of ionic magnesium for humans is 350 mg. Magnesium deficiencies have been documented in many segments of the world population. It is estimated that the average adult in Western society has a dietary magnesium shortfall of 90-178 mg per day. This fundamental deficiency is more clearly serious in those who already suffer from atherosclerosis, primary vasospastic vasculopathies or other diseases with a vasospastic component. Ionic magnesium deficiencies are particularly prevalent among diabetics with normal renal function, alcoholics, smokers, the elderly, and those who suffer from a variety of gastrointestinal motility or absorption disorders.
Ionic magnesium in mammals resides in three compartments: (1) in bone; (2) in an intracellular bound form (for example, in ionic linkage with an anionic substrate) or an intracellular unbound form; and (3) in circulating bound and unbound forms. When the concentration of circulating magnesium in the bloodstream increases as a result of the dietary uptake of magnesium, the body quickly responds by sequestering the magnesium into one of the bound or intracellular forms listed above. If elemental magnesium is ingested in a bulk amount which results in the absorption of a magnesium bolus in excess of 8 mEq, the renal excretion of magnesium rapidly increases and, as a result, becomes less efficient in the resorption of this element. Thus, the accurate sustenance of an appropriate magnesium level requires the repeated administration of carefully designed ionic-magnesium-containing medicaments with correctly formulated, absorption targeted amounts.
At the present time, a sustained elevation of magnesium can be attained only by the repeated consumption of a bewildering variety of magnesium-containing tablets. Unfortunately, available products are frequently either unclear or inaccurate in specifying their formulation or in specifying the amount of ionic magnesium they provide, or they make available ionic magnesium in amounts below or above the ideal (frequently greatly below or above appropriate levels). For these reasons, it has proved clinically difficult rationally to administer elemental magnesium in a manner permitting it to achieve its full potential as therapy for the control of vasoconstriction and the various diseases and conditions giving rise to or otherwise associated with vasoconstriction. This invention, by virtue of its careful selection of appropriate components with complementary therapeutic effects, delivered at specified dosage levels targeted for suitable gastrointestinal absorption, eliminates the current confusion about correct product selection and the frequent clinical use of inappropriate doses.